Glucocorticoid (GC) drugs have profound anti-inflammatory and immunosuppressive properties that are useful for treating a wide variety of chronic conditions including, for example, rheumatoid arthritis, inflammatory bowel disease, lupus erythematosus and asthma. Synthetic GCs are among the most widely prescribed drugs in the world. The therapeutic usage of glucocorticoids has risen continuously in recent years. Each year 10 million new prescriptions are written for oral corticosteroids in the United States. Overall, the total market size is considered to reach about 10 billion US dollars per year.
Unfortunately, the development of major side effects remains a key limitation for the long-term therapeutic use of GCs. Common side effects of GCs that require, for example, dosage adjustment or removal from therapy include, insulin resistance, hyperglycemia, diabetes, for example, steroid diabetes, fatty liver (hepatosteatosis), hypertension, bone loss, for example, osteoporosis and muscle wasting. For example, a study has shown that patients receiving high-dose glucocorticoid therapy lost a mean of 27% of their lumbar spine bone density during the first year of treatment.1 Another study showed that up to 50% of patients receiving GC treatment required insulin as a result of GC-induced diabetes.2 
Table 1 outlines the current treatments used to reduce GC-induced side effects. These combination therapies are known to have inherent side effects and/or deficiencies in therapeutic outcome.
Hepatic glucose production is essential for survival during times of stress, fasting and starvation. In response to stress, GCs are released from the adrenal cortex, increasing the expression of gluconeogenic genes through activation of the glucocorticoid receptor (GR) in the liver. During fasting, glucagon is secreted from the α-cells of the pancreatic islets. Glucagon signals for the utilization of liver glycogen stores to maintain normoglycemia while also protecting against hypoglycemia through upregulation of genes in the gluconeogenic pathway.
Insulin is the dominant suppressor of gluconeogenesis in response to feeding. Complex signaling orchestrated by fasting, stress and feeding hormones tightly regulate expression of enzymes involved in the gluconeogenic pathway. Several genes regulated by GR in the liver include phosphoenolpyruvate carboxykinase (Pepck) and glucose-6-phosphatase (G6Pc). Pepck and its regulation have been extensively studied due to its importance in hepatic glucose output during fasting and in diabetes.3 Its expression is mainly regulated at the transcriptional level by complex hormonal and dietary stimuli. Under normal conditions, after a meal, an increase in circulating glucose stimulates insulin secretion from the pancreatic β-cells. In the liver, increased circulating insulin inhibits Pepck transcription through Akt-mediated phosphorylation of FOXO1, resulting in inactivation of this transcription factor and ultimately a suppression of hepatic glucose production.4 Conversely, Pepck expression is induced in response to fasting through the actions of increased circulating glucagon and GCs.5 In contrast to the effects of GCs in the liver, studies in diabetic animal models have shown that activation of the liver X receptor (LXR) (with a synthetic agonist) improves glucose tolerance and reduces hepatic glucose output by downregulating the expression of Pepck, G6Pc, 11β-hydroxysteroid dehydrogenase type 1 and GR.6,7 
Multiple interactions of regulatory factors and co-activators have been characterized within the first 1.5 kb region upstream of the transcription start site (TSS) on the rat Pepck promoter.5 Induction of Pepck gene expression by GCs is mediated through the complex glucocorticoid response unit (GRU). The GRU is composed of two low affinity, non-consensus GR binding sites (GRE1 and GRE2), a cAMP response element (CRE) binding site, three adjacent glucocorticoid receptor accessory factor binding sites (gAF1, gAF2 and gAF3) and two distal accessory binding sites.4,8,9,10,11,12 
Several studies have shown that the binding of accessory factors FOXO1, HNF4α, COUP-TF, PPARγ2, PPARα and RXRα/RAR to the glucocorticoid receptor accessory factor binding sites facilitates the binding of GR to the Pepck promoter non-consensus GRE and is necessary for full GC-induced Pepck expression.11, 13 Several coactivators including PGC1α, GRIP-1, SRC-1 and CBP/p300 are also involved in Pepck transactivation, but not all of the coactivators are obligatory for GC-induced Pepck expression.5,14 
Moreover, the GRU of the Pepck promoter also encompasses a cAMP response unit and a retinoic acid response unit. Furthermore, the gAF2 region of GRU is also a part of the insulin response unit of the gene.9,15,16 This indicates that the GRU is a more global regulatory element in which all of the sites act in a synergistic manner to control the transcription of the Pepck gene in response to GCs, glucagon, insulin and retinoic acids.
In contrast to the induction of Pepck with GR activation, activation of LXRα by a synthetic ligand (GW3965) represses Pepck expression in mouse liver.6 Herzog et al. (2007) also showed in a human hepatoma cell line (Huh7) that activation of LXR by a synthetic potent ligand T0901317, recruits LXR and a co-repressor (RIP140) to the endogenous Pepck promoter (gAF3 region) to repress transcription.17 Together, these studies demonstrate that activation of GR and LXRα reciprocally regulate liver gluconeogenesis.
Mice which lack the expression of LXRβ or both LXRα and LXRβ were found to be resistant to developing dexamethasone (Dex)-induced hyperglycemia, hyperinsulinemia and hepatic steatosis but were still sensitive to the immunosuppressive effects of Dex.18 
Cushing's syndrome is most frequently caused by a pituitary adenoma that hypersecretes the trophic factor ACTH. In response to ACTH, the adrenal gland becomes enlarged and is stimulated to produce excess cortisol (a glucocorticoid (GC) hormone). Because the pituitary tumour is insensitive to feedback inhibition by cortisol, the stimulating effect of ACTH continues uninterrupted. As such, Cushing's syndrome patients have high circulating endogenous GC levels and many cases present with symptoms of abnormal fat distribution, insulin resistance, hyperglycemia, hypertension (70-90%)19, 20; proximal myopathy (30-80%)19, 21; and osteoporosis (40%-70%)19, 22, 23, 24.